Resistance to anticancer agents is a major cause of chemotherapeutic failure in cancer. (M. K. Rosenberg et al., Structure, 2010, 18, 482.) The 75 kDa human breast cancer resistance protein (BCRP) is a polytopic plasma membrane transport protein that has been detected in many drug-resistant cell lines, solid tumors, and hematological malignancies. BCRP (encoded by ABCG2, also known as ABCG2 and MXR (mitoxantrone-resistance protein)), an ATP-binding cassette transporter, is one of the most important transporters involved in multi-drug resistance. (Id.) BCRP expression in cancer cells confers drug-resistance in leukemia and higher levels are reported in solid tumors from the adenocarcinomas of the digestive tract, endometrium, lung and melanoma. Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material. (Diestra, J. E., et al., J Pathol, 2002. 198(2): p. 213-9.)
Ko143 is a novel fumitremorgin C analogue and reported to be a more potent and specific inhibitor than other known inhibitors of BCRP such as novobiocin, tariquidar (XR9576), elacridar (GF120918), gefitinib and imatinib. (J. D. Allen et al., Mol. Cancer Ther., 2002, 1, 417; A. Pick et al., Bioorg. Med. Chem. Lett., 1999, 9, 595.) Importantly, Ko143 is nontoxic at effective in vitro and in vivo concentrations. (J. D. Allen et al.) Subsequent routes for the synthesis of Ko143 have been reported. (Y. Li et al., Tetrahedron Lett., 2008, 49, 1480; C. Q. Xia et al., Selectivity of commonly used CYP3A4 and efflux transporter inhibitors. The 13th North American ISSX Meeting, Maui, Hi. (2005). Drug Metabolism Review. Vol 37 (suppl 2): p304 (#556)).
According to draft guidance from the United States Food and Drug Administration (“FDA”), both P-gp (P-glycoprotein, ABCB1, MDR1), another ATP-binding cassette transporter, and BCRP are expressed in the gastrointestinal tract, liver, and kidney, and have a role in limiting oral bioavailability. Therefore, investigational drugs with low permeability should be evaluated in vitro to determine whether they are potential substrates of P-gp or BCRP. (Notice, Draft Guidance for Industry on Drug Interaction Studies—Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations, 77 FR 9946, Feb. 21, 2012.) Thus, it would be beneficial to check disposition of drugs in animals with specific BCRP inhibitors.